The personal, social and criminal ramifications of psychostimulant and opioid abuse are enormous problems in North America. Clarifying the neural substrates that underlie addiction to drugs of abuse is critical for designing rational pharmacological interventions with the potential to cure addicts. A point in the cycle of addiction where pharmacological intervention can be particularly beneficial is to interfere with the overwhelming desire by addicts to use drugs. Thus, identifying the neurobiological underpinnings for engaging drug-seeking may provide novel pharmacological treatments of addiction. This proposed Neurobiology of Addiction Research Center (NARC) uses a rat model of cocaine drug-seeking behavior and unites an assemblage of investigators with expertise in behavior, neurochemistry, cell signaling and molecular biology. A core facility will generate animals having a history of stable cocaine intravenous self-administration that have been withdrawn from drug in a behavioral extinction paradigm. After various withdrawal periods, the animals will undergo a drug-primed reinstatement and be dispersed to the various projects for neurobiological evaluations. This core facility will insure consistency in experimental subjects and tissue samples amongst the projects, thereby permitting more accurate associations to be made between addiction related changes in gene expression, cell signaling, physiology, and behavior. Another aspect of the project that will be held constant is the examination of the same limbic-motor circuit that has become recognized as critical in the addiction process. Project #1 uses behavioral reinstatement to identify nuclei necessary for drug-seeking behavior that will be examined in all other projects. Project #2 will perform mRNA and protein measurements in these nuclei to identify cellular components of drug-seeking behavior. Project #3 measures monoamine transporter trafficking based in part upon findings from Projects #1 and 2. Finally, Project #4 will examine novel treatments derived from findings in the first 3 projects that possess potential for inhibiting drug-seeking behavior. In addition to this highly integrated, multi-disciplinary approach to the neurobiology and treatment of drug-seeking behavior, the NARC (via Administrative Core) will facilitate scientific interactions, provide oversight and mentor junior faculty, pre- and postdoctoral trainees and undergraduates. In part this will be accomplished through Pilot Core which will directly promote involvement of young investigators and established investigators currently outside the field of addiction to evaluate promising novel hypotheses related to the neurobiology of relapse. In summary, the NARC provides for an integrated, multidisciplinary research assault on the neurobiology of drug seeking behavior and describes a mechanism for evaluating novel pharmacological interventions. The NARC also takes advantage of the rapid growth in basic neuroscience at MUSC, as well as the existing clinical strengths in addiction research to provide a means for actively mentoring faculty and trainees.